Project Overview Transplantation tolerance Is a dynamic immunological state that accommodates graft acceptance whilst maintaining undiminished immune responses to pathogens. We have recently demonstrated that the induction and preservation of transplantation tolerance can be differentially Impacted by pathogens that elicit distinct innate and adaptive immune signatures. These and other recent observations from our laboratories have led us to hypothesize that the quality of the tolerant state, either at the time of induction or during the maintenance phase, and the type of infection determine the long-term fate of the allograft. This is a new application requesting support for a highly integrated program project focused on understanding the cellular mechanisms in T cells that are necessary for a robust and persistent state of transplantation tolerance (i.e., tolerance that resists reversal by infections and permits long-term preservation of allograft function) (Project 1; Alegre) and understanding the short-term and long-term effects of infections on an already established state of transplantation tolerance (Project 2; Chong). Two Cores support the work of the two projects in the program. The Administrative Core (Core A, Chong) will oversee the administration of the program including the coordination of Progress Reports and co-ordinate meetings with the Internal and External Advisory Boards. The Animal and Microsurgery Core (Core B, Alegre) will be responsible for animal breeding and heart transplantations necessary for the two scientific projects. The Alegre and Chong laboratories have already been functioning as an integrated, cooperative program. Our investigations are revealing the complexity of the tolerant state as well as an unexpectedly divergent impact of infections on tolerance. There are few existing paradigms to guide these studies, thus the formal infrastructure of a Program Project will allow us to more seamlessly share personnel, data, resources, and to generate new hypotheses. Interactions with the internal and external advisory board members will allow new hypotheses and research designs to be vigorously vetted and improved upon. Successful completion of this program project will result in novel mechanistic and diagnostic insights into how transplantation tolerance can persist inspite of recurrent infections and achieve long-term allograft survival superior to current therapies.